Benzimidazole compounds containing aromatic substituents, processes for their preparation and uses thereof

Abstract

The present application relates to an aromatic-substituted benzimidazole compound, a cis-trans isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The present application also relates to a method for preparing an aromatic-substituted benzimidazole compound, and the use of the aromatic-substituted benzimidazole compound as a soluble epoxide hydrolase inhibitor. The aromatic-substituted benzimidazole compounds described herein exhibit extremely high inhibitory activity against soluble epoxide hydrolase, with IC 50 values in the nanomolar range or even lower.

Description

Technical Field

[0001] This application relates to the fields of biomedicine and soluble epoxide hydrolase inhibitors. Specifically, this application relates to a benzimidazole compound containing an aromatic substituent, a method for preparing the benzimidazole compound containing the aromatic substituent, and the use of the benzimidazole compound containing the aromatic substituent as a soluble epoxide hydrolase inhibitor. Background Technology

[0002] Soluble epoxide hydrolases (sEHs) play a central role in the metabolism of bioactive lipid signaling molecules. Specific sEH hydrolases convert the substrate epoxide eicosatrienoic acid (EET) into the less bioactive dihydroxyeicosatrienoic acid (DHETA). These EETs are ubiquitous in endothelial cells, kidneys, and lungs. Compared to many end products of the prostaglandin and leukotriene pathways, EETs possess anti-inflammatory, analgesic, antihypertensive, cardioprotective, and organ-protective properties. Although EETs have effective in vivo activity, their efficient accumulation in vivo is hindered by the high catalytic activity of sEHs. Therefore, sEH inhibition is an effective strategy for addressing these various indications. Inhibition of sEHs has been found to significantly reduce blood pressure in mammals and promote inflammation resolution by reducing the production of inflammatory factors (NOs), cytokines, and lipid mediators. Several small molecule compounds have been identified as therapeutic strategies for various diseases in animals and humans by inhibiting sEH activity and increasing EET levels.

[0003] International publication number WO2021242790A1 discloses a benzimidazole compound that can be used as a soluble epoxide hydrolase inhibitor. In an in vitro activity test using human sEH and its substrate PHOME as model compounds, the soluble epoxide hydrolase inhibitor showed an IC50 of [missing information - likely related to an IC50 value]. 50 The value is less than 1 μM. Summary of the Invention

[0004] The purpose of this application is to provide a benzimidazole compound containing aromatic substituents that can be used as a soluble epoxide hydrolase inhibitor. Specifically, in the benzimidazole compound containing aromatic substituents described herein, at least one unsaturated carbon atom in the benzene ring of the benzimidazole structure is directly connected to an unsaturated carbon atom of a first aromatic substituent, and the carbon atom in the imidazole ring of the benzimidazole structure that is adjacent to two N atoms is directly connected to an unsaturated carbon atom of a second aromatic substituent.

[0005] The purpose of this application is also to provide a method for preparing the benzimidazole compound containing aromatic substituents as described above.

[0006] The purpose of this application is also to provide the use of the benzimidazole compound containing aromatic substituents as described above as a soluble epoxide hydrolase inhibitor.

[0007] The purpose of this application is also to provide a pharmaceutical composition comprising, as described above, a benzimidazole compound containing an aromatic substituent and a pharmaceutically acceptable carrier, excipient, or excipient.

[0008] This application also aims to provide a kit comprising a benzimidazole compound or pharmaceutical composition containing an aromatic substituent as described above. Furthermore, this application aims to provide the use of the benzimidazole compound containing an aromatic substituent as described above in the preparation of a medicament for sEH-mediated diseases.

[0009] The purpose of this application is also to provide a method for preventing or treating sEH-mediated diseases.

[0010] To address the aforementioned technical problems, this application provides the following technical solution.

[0011] In a first aspect, this application provides a benzimidazole compound containing an aromatic substituent, its cis-trans isomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug, characterized in that the benzimidazole compound containing the aromatic substituent has a structure represented by the following general formula IA or general formula IB:

[0012]

[0013] In this context, X and Y each independently represent C or N;

[0014] R1, R2 and R3 are each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes.

[0015] R9 is selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes, or groups of a prodrug of the parent structure.

[0016] Ar1 and Ar2 are each independently selected from the group consisting of substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups.

[0017] In this structure, at least one unsaturated carbon atom in the benzene ring of the benzene structure is directly connected to an unsaturated carbon atom of Ar1, and the carbon atom in the imidazole ring of the benzene structure that is adjacent to two N atoms is directly connected to an unsaturated carbon atom of Ar2.

[0018] In one embodiment of the first aspect, the benzimidazole compound containing an aromatic substituent has a structure represented by the following general formula IIA or IIB:

[0019]

[0020] Among them, R4, R5, R6, R 11 and R 12 Each is independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes.

[0021] In one embodiment of the first aspect, R1 and R2 are connected to form a five-membered ring, a six-membered ring, a seven-membered ring, or an eight-membered ring.

[0022] And / or, R4 and R5 are connected to form a quinary ring, a hexagram, a septum, or an octum;

[0023] And / or, R4 and R6 are connected to form a quinary ring, a hexagram, a septum, or an octum.

[0024] In one embodiment of the first aspect, Ar1 has a structure as shown by the following general formula III:

[0025]

[0026] A1, A2, A3, A4 and A5 are each independently selected from the group consisting of CR, N, N-OR, S and O, wherein R is each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes.

[0027] In one embodiment of the first aspect, Ar1 has a structure as shown by the following general formula IV:

[0028]

[0029] A6, A7, A8, A8, and A9 are each independently selected from the group consisting of CR, N, N-OR, S, and O, where R is each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes.

[0030] In one embodiment of the first aspect, the benzimidazole compound containing an aromatic substituent is selected from the group consisting of:

[0031]

[0032]

[0033]

[0034]

[0035] In a second aspect, this application provides a benzimidazole compound containing an aromatic substituent as described in the first aspect, the use of its cis-trans isomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug as a soluble epoxide hydrolase inhibitor.

[0036] In a third aspect, this application provides a pharmaceutical composition comprising a benzimidazole compound containing an aromatic substituent as described in the first aspect, its cis-trans isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, excipient or excipient.

[0037] In a fourth aspect, this application provides a kit comprising a benzimidazole compound containing an aromatic substituent as described in the first aspect, its cis-trans isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition as described above.

[0038] In a fifth aspect, this application provides the use of a benzimidazole compound containing an aromatic substituent as described in the first aspect, its cis-trans isomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug in the preparation of a medicament for treating sEH-mediated diseases.

[0039] In a sixth aspect, this application provides a method for preparing a benzimidazole compound containing an aromatic substituent as described in the first aspect, characterized in that the method comprises the following steps:

[0040] S1: React the halo-o-phenylenediamine precursor with the benzaldehyde precursor to obtain the benzimidazole intermediate;

[0041] S2: React the benzimidazole intermediate with the boric acid precursor to obtain the benzimidazole compound containing aromatic substituents;

[0042] The halo-o-phenylenediamine precursor has a structure represented by the following general formula (1):

[0043]

[0044] The benzaldehyde precursor has a structure represented by the following general formula (2):

[0045]

[0046] The benzimidazole intermediate has a structure represented by the following general formula (3):

[0047]

[0048] The boric acid precursor is Ar1-B(OH)2, or has a structure represented by the following general formula (4):

[0049]

[0050] Wherein, R1, R2, R3, R4, R5 and Ar1 are as defined in claim 1;

[0051] Where M represents halogen.

[0052] Compared with the prior art, the beneficial effect of this application is that in the benzimidazole compound containing aromatic substituents described herein, at least one unsaturated carbon atom in the benzene ring of the benzimidazole structure is directly connected to the unsaturated carbon atom of the first aromatic substituent, and the carbon atom in the imidazole ring of the benzimidazole structure adjacent to two N atoms is directly connected to the unsaturated carbon atom of the second aromatic substituent. This makes the benzimidazole compound containing aromatic substituents exhibit extremely high inhibitory activity against soluble epoxide hydrolases, IC50. 50 The value is on the nanomolar scale or even lower. Attached Figure Description

[0053] Figure 1 This demonstrates a general synthetic route for benzimidazole compounds containing aromatic substituents according to the present invention. Detailed Implementation

[0054] Terminology Definition

[0055] It should be understood that the terminology used herein is for the purpose of describing specific implementation schemes and is not intended to be limiting.

[0056] As used herein, the term "acyl" represents hydrogen or an alkyl group as defined herein, which is attached to a parent molecule group by a carbonyl group as defined herein, and is composed of a formyl group (i.e., a formaldehyde group), an acetyl group, a trifluoroacetyl group, a propionyl group, and a butyryl group. Exemplary unsubstituted acyl groups include 1 to 6, 1 to 11, or 1 to 21 carbon atoms.

[0057] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group with 1-20 carbon atoms (e.g., 1-16 carbon atoms, 1-10 carbon atoms, or 1-6 carbon atoms). Alkylene is a divalent alkyl group.

[0058] As used herein, the term "alkenyl" alone or in combination with other groups refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2-20 carbon atoms (e.g., 2-16 carbon atoms, 2-10 carbon atoms, 2-6, or 2 carbon atoms).

[0059] As used herein, the term "alkynyl" alone or in combination with other groups refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2-20 carbon atoms (e.g., 2-16 carbon atoms, 2-10 carbon atoms, 2-6, or 2 carbon atoms).

[0060] As used herein, the term "amino" represents –N(RN1)2, wherein each RN1 is independently H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or other groups described herein), wherein each of these described RN1 groups may optionally be substituted; or two RN1s may be combined to form an alkylene or heteroalkylene, wherein each RN2 is independently H, alkyl, or aryl. The amino groups of the present invention may be unsubstituted amino groups (i.e., –NH2) or substituted amino groups (i.e., –N(RN1)2).

[0061] As used herein, the term "aryl" refers to an aromatic monocyclic or polycyclic aromatic group having 6-12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indenyl, and 1H-indenyl.

[0062] As used herein, the term "aromatic substituent" refers to an aromatic unsaturated substituent, which may be a substituted or unsubstituted group comprising 5-12 carbon atoms. For example, an aromatic substituent may be a substituted or unsubstituted five-membered or six-membered ring structure, and the ring-forming atoms may include one or more of carbon, nitrogen, oxygen, and sulfur atoms.

[0063] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are those with 7 to 30 carbon atoms (e.g., from 7 to 16 or from 7 to 20 carbon atoms, such as C1-6 alkyl and C6-alkyl). 10 Aryl, C1- 10 Alkyl C6- 10 Aryl, or C1- 20 Alkyl C6- 10 Aryl groups, such as benzyl and phenethyl. In some embodiments, the alkyl and aryl groups may each be further substituted with one, two, three, or four substituents as defined herein for their respective groups.

[0064] As used in this article, the term "cyano" represents the –CN group.

[0065] As used in this article, the term "carbocyclic group" refers to a non-aromatic C3- group. 12 Monocyclic, bicyclic, or tricyclic structures, wherein the rings are formed from carbon atoms. Carbocyclic structures include cycloalkyl and unsaturated carbocyclic groups.

[0066] As used herein, the term "cycloalkyl" refers to a saturated, non-aromatic monovalent single-carbon cycloalkyl or multi-carbon cycloalkyl group with 3-10, preferably 3-6 carbon atoms. This term is further illustrated by examples of groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0067] As used in this article, the term "halogen" refers to a fluorine (fluorinated), chlorine (chlorinated), bromine (brominated), or iodine (iodinated) group.

[0068] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, wherein one or more constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with one, two, three, or four substituents as described herein for alkyl groups. "Alkoxy" represents all branched and straight-chain isomers with a specific number of carbon atoms, wherein the terminal hydrogen atom is replaced by an oxygen atom. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.

[0069] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein, wherein one or more constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group may be further substituted with one, two, three, or four substituents as described herein for the alkenyl group.

[0070] As used herein, the term "heterynyl" refers to an ynyl group as defined herein, wherein one or more constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heterynyl group may be further substituted with one, two, three, or four substituents as described herein for the ynyl group.

[0071] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic group having 5-12 atoms of at least one aromatic ring containing one, two, or three cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of a heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridinyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0072] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are those with 7 to 30 carbon atoms (e.g., from 7 to 16 or from 7 to 20 carbon atoms, such as C10). 1-6 Alkyl C 2-9 heteroaryl, C 1-10 alkyl C2-9 heteroaryl, or C 1-20 Alkyl C 2-9(Heteroaryl). In some embodiments, the alkyl and heteroaryl groups may each be further substituted with one, two, three, or four substituents as defined herein for their respective groups.

[0073] As used herein, the term "heterocyclic group" refers to a monocyclic or polycyclic group having 3 to 12 atoms, containing at least one ring of 1, 2, 3, or 4 cyclic heteroatoms selected from N, O, or S, wherein none of the rings is aromatic. Examples of heterocyclic groups include, but are not limited to, morpholino, thiomorpholino, furanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxane.

[0074] As used herein, the term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group. Exemplary unsubstituted heterocyclic alkyl groups are those with 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C). 1-6 Alkyl C 2-9 Heterocyclic group, C 1-10 Alkyl C 2-9 Heterocyclic group, or C 1-20 Alkyl C 2-9 Heterocyclic groups). In some embodiments, the alkyl and heterocyclic groups may each be further substituted with one, two, three, or four substituents as defined herein for their respective groups.

[0075] As used herein, the term "hydroxyl" represents a -OH group. The term "thiol" as used herein represents a -SH group.

[0076] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclic (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclic groups can be substituted or unsubstituted. When substituted, there will typically be 1-4 substituents present unless otherwise specified. Substituents include, for example: aryl (e.g., substituted and unsubstituted phenyl), carbocyclic (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluorinated), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclic, amino (e.g., NH2 or mono- or dialkylamino), azide, cyano, nitro, or mercapto. Aryl, carbocyclic (e.g., cycloalkyl), heteroaryl, and heterocyclic groups can also be substituted with alkyl groups (unsubstituted and substituted, e.g., arylalkyl (e.g., substituted and unsubstituted benzyl)).

[0077] In the practice of the method of the present invention, an "effective amount" of any of the compounds of the present invention or any combination of the compounds of the present invention or their pharmaceutically acceptable salts is given by any commonly used and acceptable method known in the art (alone or in combination).

[0078] As used herein, the term "epoxyeicosatetrienoic acid" refers to a signaling molecule formed by the action of cytochrome P450 cyclooxygenase on 20-carbon essential fatty acids, such as arachidonic acid. "Dihydroxyeicosatetrienoic acid" is, for example, the corresponding vicinal diol produced by the hydrolysis of epichlorohydrin by soluble epoxide hydrolases. As used herein, the term "increased epichlorohydrin levels" means an increase in the total epichlorohydrin level in a subject after administration of the compounds of the present invention compared to the pre-administration level. As used herein, the term "decreased dihydroxyeicosatetrienoic acid levels" means an increase in the total dihydroxyeicosatetrienoic acid level in a subject after administration of the compounds of the present invention compared to the pre-administration level.

[0079] As used in this article, the term "inhibition of soluble epoxide hydrolase" refers to the inhibition of enzymes with IC50-6-hydroxylase (IC50) 50 Enzymatic activity of soluble epoxide hydrolases at concentrations less than 10 μM (e.g., less than 5 μM, less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM). The enzymatic activity of soluble epoxide hydrolases can be determined using any method known in the art; for example, the activity can be determined using an assay with (3-phenyl-epoxyethylene)-cyanoacetate-(6-methoxy-naphth-2-yl)-methyl ester (PHOME) as a substrate. In this specific assay, the epoxide hydrolase hydrolyzes PHOME to produce highly fluorescent 6-methoxy-2-naphthaldehyde, which can be analyzed using an excitation wavelength of 330 nm and an emission wavelength of 465 nm.

[0080] As used herein, the term "pharmaceutical composition" means a composition containing the compounds described herein formulated with pharmaceutically acceptable excipients and manufactured or sold with the approval of a government regulatory agency as part of a treatment regimen for the treatment of mammalian diseases. Pharmaceutical compositions may be formulated, for example, in unit dosage forms for oral administration (e.g., tablets, capsules, pouches, soft capsules, or syrups); for topical administration (e.g., as creams, gels, lotions, or ointments); for intravenous administration (e.g., as microparticle-free emboli and as sterile solutions in solvent systems suitable for intravenous use); or as any other pharmaceutically acceptable formulation. As used herein, "pharmaceuticalally acceptable excipients" refers to any ingredient that is not a compound described herein (e.g., a medium capable of suspending or dissolving the active compound) and has properties that are substantially non-toxic and non-inflammatory in patients. Excipients may include, for example: anti-adhesives, antioxidants, binders, coatings, tableting aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, aroma enhancers, flow aids (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending agents or dispersants, sweeteners, and water for hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (binary), calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0081] As used herein, the term "pharmaceuticalally acceptable salt" means any pharmaceutically acceptable salt of a compound of formula (I). For example, a pharmaceutically acceptable salt of any compound described herein includes those suitable for use in contact with tissues of humans and animals without excessive toxicity, irritation, anaphylactic reactions, and in proportion to a reasonable benefit / risk ratio, within the bounds of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.S. Stahl and C.W. Germuth), Wiley-VCH, 2008. Salts may be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

[0082] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or the salts may (in the case of the acidic form of the compounds of the present invention) be prepared from inorganic or organic bases. Frequently, the compounds are prepared as or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing suitable salts are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases (including inorganic and organic acids and bases).

[0083] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheponicate, glyceryl phosphate, hemisulfate, heptasulfate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0084] As used herein, the term "subject" means any organism to which the compositions according to the invention may be administered, for example, for experimental, diagnostic, preventative, and / or therapeutic purposes. Typical subjects include any animal (such as mammals such as mice, rats, rabbits, non-human primates, and humans). Subjects may be seeking or needing treatment, require treatment, are receiving treatment, will receive treatment in the future, or are persons or animals being cared for by trained professionals for a particular disease or condition.

[0085] As used herein, the term "treatment" or "therapeutic" means therapeutic treatment and preventative or preventive measures in which the goal is to prevent or delay (mitigate) an unwanted physical symptom, disorder, or disease, or to achieve a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction of the severity of the symptom, disorder, or disease; stabilization (i.e., non-deterioration) of the state of the symptom, disorder, or disease; delay or slowing of the onset of the progression of the symptom, disorder, or disease; improvement or remission (whether partial or complete), whether detectable or undetectable; improvement of at least one measurable physiological parameter, which need not be identifiable to the patient; or improvement or enhancement of the symptom, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonged survival compared to the expected survival if treatment had not been received.

[0086] Various small molecule compounds have been discovered that can inhibit sEH activity and increase EET levels, thereby preventing and treating sEH-mediated diseases in animals and humans. For example, existing literature has disclosed that sEH inhibitors may have beneficial effects in the treatment of COPD, cardiovascular disease, diabetes, and even Alzheimer's disease. Therefore, there is an ongoing need in the field to develop soluble epoxide hydrolase inhibitors with higher activity.

[0087] This article describes a benzimidazole compound containing an aromatic substituent, a method for preparing the benzimidazole compound containing an aromatic substituent, and its use as a small molecule inhibitor of soluble epoxide hydrolase (sEH). Because the benzimidazole compounds containing aromatic substituents described herein can readily penetrate across the blood-brain barrier, they can effectively treat not only non-central nervous system disorders (e.g., hypertension, cardiovascular and cerebrovascular diseases) but also CNS disorders (e.g., neurodegenerative diseases) and inflammation.

[0088] compound

[0089] In one specific embodiment, this application provides a benzimidazole compound containing an aromatic substituent, including its cis-trans isomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug. The benzimidazole compound containing the aromatic substituent has a structure represented by the following general formula IA or general formula IB:

[0090]

[0091] In general formulas IA and IB, X and Y independently represent C or N. In one specific embodiment, X and Y are both carbon atoms, or X and Y are both nitrogen atoms. In another embodiment, X is a carbon atom and Y is a nitrogen atom. In yet another embodiment, X is a nitrogen atom and Y is a carbon atom.

[0092] In general formulas IA and IB, R1, R2, and R3 are each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes. It should be noted that when X is a nitrogen atom, the R1 group is absent. Similarly, when Y is a nitrogen atom, the R3 group is absent. In a preferred embodiment, R1, R2, and R3 are each independently selected from the group consisting of: hydrogen, fluorine, and chlorine. Preferably, R2 is fluorine, and R1 and R3 are hydrogen.

[0093] In general formulas IA and IB, R9 is selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes, or groups of the prodrug of the parent structure.

[0094] In general formulas IA and IB, Ar1 and Ar2 are each independently selected from the group consisting of substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups. At least one unsaturated carbon atom in the benzene ring of the benzimazole structure is directly bonded to the unsaturated carbon atom of Ar1, and the carbon atom in the imidazole ring of the benzimazole structure that is adjacent to two N atoms is directly bonded to the unsaturated carbon atom of Ar2.

[0095] In one specific embodiment, the benzimidazole compound containing an aromatic substituent has a structure represented by the following general formula IIA or IIB:

[0096]

[0097] In general formulas IIA and IIB, R4, R5, R6, R 11 and R 12 Each is independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes.

[0098] In one embodiment, R1 and R2 are connected to form a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In another embodiment, R4 and R5 are connected to form a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In yet another embodiment, alternatively or additionally, R4 and R6 are connected to form a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring.

[0099] In one specific embodiment, Ar1 has a structure as shown by the following general formula III:

[0100]

[0101] In general formula III, A1, A2, A3, A4 and A5 are each independently selected from the group consisting of CR, N, N-OR, S and O, wherein R is each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes.

[0102] In a preferred embodiment, Ar1 has a structure represented by the following general formula IV:

[0103]

[0104] In general formula IV, A6, A7, A8, A8 and A9 are each independently selected from the group consisting of CR, N, N-OR, S and O, wherein R is each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, trifluoromethyl, alkoxy, cycloalkoxy, aryloxy, substituted or unsubstituted amino, substituted or unsubstituted mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or their isotopic substitutes.

[0105] In a particularly preferred embodiment, the benzimidazole compound containing an aromatic substituent is selected from the group consisting of:

[0106]

[0107]

[0108]

[0109]

[0110] In this document, the terms alkyl, alkenyl, and ynyl include straight-chain or branched monovalent substituents. Examples of these include methyl, ethyl, isobutyl, 3-butynyl, etc. Examples of groups that can be used in the compounds and methods described herein may include C1-C1 groups. 20 Alkyl, C2-C 20 alkenyl and C2-C20 Alkynyl. The terms heteroalkyl, heteroalkenyl, and heteroynyl are defined similarly to alkyl, alkenyl, and ynyl, but their backbone may include O, S, N heteroatoms or combinations thereof.

[0111] The terms cycloalkyl, cycloalkenyl, and cycloynyl groups include cycloalkyl groups having one or more fused rings. Examples of these groups may include cyclohexyl, cyclopentylethyl, and adamantyl. The terms heterocycloalkyl, heterocycloalkenyl, and heterocycloynyl are defined similarly to cycloalkyl, cycloalkenyl, and cycloynyl groups, but their backbone may include O, S, N heteroatoms or combinations thereof.

[0112] Aryl molecules can include cyclic hydrocarbons, which may comprise one or more flat groups of carbon atoms (typically six) linked together by an equal number of delocalized electrons, as if they were composed of alternating single and double bonds. An example of an aryl molecule is a benzene ring. In heteroaryl molecules, the carbon atoms forming the ring can be substituted with O, N, or S. When a heteroatom is introduced, five groups of atoms (e.g., four carbon atoms and one heteroatom) can form an aromatic system. Examples of heteroaryl molecules include furans, pyrroles, thiophenes, imidazoles, oxazoles, pyridines, and piperazines. Aryl and heteroaryl molecules may also include additional fused rings, such as benzofuran, indole, benzothiophene, naphthalene, anthracene, and quinoline. Unless otherwise stated, aryl and heteroaryl groups can be linked at any position.

[0113] The alkoxy, cycloalkoxy, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, heteroaryl, cycloalkyl, or heterocycloalkyl groups described herein may be substituted or unsubstituted. As used herein, the term "substituted" refers to the addition of an alkoxy, cycloalkoxy, aryloxy, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, heteroaryl, cycloalkyl, or heterocycloalkyl group to the backbone of the alkoxy, cycloalkoxy, amino, alkyl, alkenyl, ynyl, aryl, heteroaryl, heteroalkenyl, heteroynyl, heteroaryl, alkyl, or heterocycloalkyl group. For example, replacing a hydrogen atom with one of these groups. Examples of substituents include, but are not limited to, hydroxyl, halogens (e.g., F, Cl, Br, or I), and carbonyl groups. Conversely, the term "unsubstituted" refers to an alkoxy, cycloalkoxy, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, heteroaryl, cycloalkyl, or heterocycloalkyl group consisting entirely of hydrogen atoms.

[0114] Preparation methods of compounds

[0115] The aromatic-substituent-containing benzimidazole compounds described herein can be prepared in various ways and synthesized through different synthetic routes. These compounds can be synthesized using readily available raw materials, and those skilled in the art can also obtain optimal reaction conditions based on the actual reaction reagents and solvents used.

[0116] As an example, Figure 1 A general route for synthesizing the aromatically substituent-containing benzimidazole compounds described herein is shown. Reference Figure 1 The method may include the following steps:

[0117] S1: React the halo-o-phenylenediamine precursor with the benzaldehyde precursor to obtain the benzimidazole intermediate;

[0118] S2: React the benzimidazole intermediate with the boric acid precursor to obtain the benzimidazole compound containing aromatic substituents.

[0119] The halo-o-phenylenediamine precursor has a structure represented by the following general formula (1):

[0120]

[0121] The benzaldehyde precursor has a structure represented by the following general formula (2):

[0122]

[0123] The benzimidazole intermediate has a structure represented by the following general formula (3):

[0124]

[0125] The boric acid precursor is Ar1-B(OH)2, or has a structure represented by the following general formula (4):

[0126]

[0127] R1, R2, R3, R4, R5, and Ar1 are as defined above. M represents halogen.

[0128] Pharmaceutical Composition

[0129] The aromatic-substituent benzimidazole compounds or their derivatives, cis-trans isomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs described herein may be provided in the form of pharmaceutical compositions. Pharmaceutical compositions may include a therapeutically effective amount of the aromatic-substituent benzimidazole compound and pharmaceutically acceptable excipients, carriers, or excipients. Depending on the intended injection modality, the pharmaceutical composition may be a solid, semi-solid, or liquid formulation. Those skilled in the art can select excipients, carriers, or excipients, as well as the dosage form of the pharmaceutical composition, as appropriate, which will not be elaborated upon here.

[0130] How to use

[0131] This application also provides a method for treating or preventing soluble epoxide hydrolase (sEH)-related diseases in a subject. The method includes injecting the subject with an effective amount of one or more compounds or pharmaceutical compositions as described herein, or a pharmaceutically acceptable salt or prodrug thereof. When used in the method, the term "effective amount" refers to the amount of a compound that enables the desired pharmacological effect and other biological effects. For example, an effective amount may be the concentration of a compound that inhibits sEH in vitro.

[0132] The benzimidazole compounds or pharmaceutical compositions containing aromatic substituents described herein may be used to treat diseases associated with or mediated by serous encephalopathy (sEH) in humans and animals. These diseases may include neurodegenerative disorders, inflammation, and hypertension.

[0133] Methods for treating or preventing sEH-related or mediated diseases in subjects may also include injecting the subject with a second compound, biomolecule, or composition. Additional reagents, as well as the aromatic-substituent benzimidazole compounds described herein, may be injected in any order.

[0134] Reagent test kit

[0135] This application also provides a kit for treating sEH-related or mediated diseases in subjects. The kit may include one or more benzimidazole compounds or pharmaceutical compositions containing aromatic substituents as described herein. The kit may also include one or more other reagents, such as anti-inflammatory drugs. The kit may be an oral or intravenous formulation made from benzimidazole compounds or pharmaceutical compositions containing aromatic substituents as described herein. The kit may also include instructions for use, a container, and a device and / or carrier for injecting the compound or composition.

[0136] use

[0137] This application also relates to the use of the aromatic-substituent-containing benzimidazole compounds described herein, their cis-trans isomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, as soluble epoxide hydrolase inhibitors. This application also relates to the use of the aromatic-substituent-containing benzimidazole compounds described herein, their cis-trans isomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, in the preparation of medicaments for treating sEH-mediated diseases.

[0138] Example

[0139] The present application will be further described and illustrated below with reference to embodiments. Unless otherwise specified, all chemical raw materials used can be purchased from the market. Those skilled in the art will understand that the following embodiments are merely exemplary.

[0140] In the following embodiments, the characterization methods used are as described below.

[0141] 1H NMR spectrum ( 1 H NMR):

[0142] Nuclear magnetic resonance spectra of reaction products and intermediates ( 1 The 1H NMR spectrum was obtained using a Bruker AVANCE IIIHD400 / 500 NMR spectrometer. Sample preparation involved completely dissolving approximately 10 mg of the sample in approximately 0.5 mL of deuterated reagent in a clean, dry glass NMR tube. Products with good solubility were dissolved in deuterated chloroform (CDCl3) at room temperature, while products with poor solubility were dissolved in deuterated dimethyl sulfoxide (DMSO-d6). DMSO-d6 tends to solidify at lower room temperatures and should be melted with a blower before sample loading. Tetramethylsilane (TMS) was used as an internal standard at room temperature, with a chemical shift of 0 ppm.

[0143] Example 1

[0144] This embodiment relates to the synthesis and characterization of benzimidazole compounds containing aromatic substituents.

[0145] refer to Figure 1 The aromatic-substituent-containing benzimidazole compounds described herein can be synthesized in two steps according to the following general procedure. A solution of Na₂S₂O₅ (4 mmol in 6 mL water) was added to a solution of a halophenyl-1,2-diamine precursor (2 mmol) and a benzaldehyde precursor (3 mmol) in EtOH (60 mL). The mixture was degassed and stirred overnight at 80 °C, then concentrated under reduced pressure. The residue was extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were washed with water. The solvent was dried over Na₂SO₄ and removed under reduced pressure. The residue was purified by column chromatography to give the corresponding benzimidazole intermediate.

[0146] To a flask containing the benzimidazole intermediate (0.1 mmol), boric acid precursor (0.12 mmol), potassium carbonate (0.36 mmol), and catalyst Pd(dppf)₂Cl₂ (0.015 mmol), 1,4-dioxane / water (2.5 mL, v / v, 9:1) obtained in the previous step, 1,4-dioxane / water was added. The mixture was degassed three times with N₂ and then microwaved (110 °C, 1 hr) for 1 hour. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated, and the residue was purified by preparative HPLC to obtain the target product, an aromatically substituent-containing benzimidazole compound.

[0147] In this embodiment, 41 novel aromatic-substituent-containing benzimidazole compounds were synthesized using the general steps described above. The corresponding structures of the benzimidazole intermediates, boric acid precursors, and the final aromatic-substituent-containing benzimidazole compounds are shown in Table 1 below. As a specific example, the halophenyl-1,2-diamine precursors used in this embodiment are all 3-bromine-substituted o-phenylenediamine precursors, with the R9 group being a hydrogen atom. The first step is a process well known in the art, therefore the specific structures of the halophenyl-1,2-diamine precursor (also referred to as: halo-o-diphenyl precursor) and benzaldehyde precursor are not shown. However, those skilled in the art can determine the specific structures of the halophenyl-1,2-diamine precursor and benzaldehyde precursor used by examining the structure of the benzimidazole intermediate.

[0148] Table 1. Structures and corresponding enzyme activities of benzimidazole intermediates, boric acid precursors, and benzimidazole compounds containing aromatic substituents in Example 1.

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] The NMR characterization data of compounds 1-41 synthesized in Example 1 are as follows.

[0156] 4-(6-(3-chloropyridin-4-yl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 1): 1 HNMR (DMSO-d6): δ = 8.47 (d, 1H, J = 4.8Hz), 8.40 (d, 2H, J = 8.4Hz), 7.96 (d, 1H, J = 4.8Hz), 7.91 (d, 2H, J = 8.4Hz), 7.71-7.53 (m, 3H), 2.65 (s, 6H).

[0157] 6-(3-chloropyridin-4-yl)-5-fluoro-2-(3-fluoro-4-methoxyphenyl)-1H-benzo[d]imidazole (compound 2): 1H NMR (DMSO-d6): δ=13.09(br,1H),8.75(s,1H),8.60(d,1H,J=4.4Hz),7.98(s,1 H), 7.96 (d, 1H, J = 3.6Hz) 7.56-7.51 (m, 3H), 7.35 (t, 1H, J = 4.8Hz), 3.90 (s, 3H).

[0158] (R)-1-(4-(6-(2-chloro-6-methylpyridin-3-yl)-5-fluoro-1H-benzo[d]imidazol-2-yl)benzoyl)piperidine-3-carboxamide (compound 3): 1 H NMR (DMSO-d6): δ = 8.20 (d, 2H, J = 8.4Hz), 7.81 (d, 1H, J = 7.6Hz), 7.53 (d, 4H, J = 8.0Hz), 7.37 (d, 1H, J = 7.6Hz) ,6.87(m,2H),4.47-4.6(m,1H),3.60-3.40(m,2H),2.98-2.82(m,2H),1.98-1.86(m,2H),1.65-1.42(m,2H).

[0159] 5-Chloro-6-(4-chloro-2-methylpyrimidin-5-yl)-2-(4-(methylsulfonyl)phenyl)-1H-benzo[d]imidazolium (compound 4): 1 HNMR (DMSO-d6): δ = 8.47 (s, 1H), 8.28 (d, 2H, J = 8Hz), 7.88 (d, 2H, J = 8Hz), 7.66 (s, 1H), 7.51 (br, 1H), 3.23 (s, 3H), 2.73 (s, 3H).

[0160] 6-(2,4-Dimethylpyrimidin-5-yl)-4,5-difluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (compound 5): 1 H NMR (DMSO-d6): δ = 8.54 (s, 1H), 8.41 (d, 2H, J = 8.0Hz), 7.94 (d, 2H, J = 8.4Hz), 7.72 (br, 1H), 2.68 (s, 3H), 2.30 (s, 3H).

[0161] 5,7-Difluoro-6-(2-methylpyrimidin-5-yl)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (compound 6): 1HNMR (DMSO-d6): δ = 8.86 (s, 2H), 8.40 (d, 2H, J = 4.4Hz), 7.94 (d, 2H, J = 8.4Hz), 7.68 (br, 1H), 2.69 (s, 3H).

[0162] 5-(5-fluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)-N,2-dimethylpyrimidin-4-amine (compound 7): 1 H NMR (DMSO-d6): δ=8.35(s,1H),8.33(d,2H,J=8.0Hz),7.87(d,2H,J=8.4Hz),7.63-7.56(m,2H),6.28(br.1H),2.98(s,3H),2.61(s,3H).

[0163] 5-(4,5-Difluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)-4-methylpyrimidin-2-amine (Compound 8): 1 H NMR (DMSO-d6): δ = 8.36 (d, 2H, J = 8.0Hz), 8.05 (s, 1H), 7.91 (d, 2H, J = 8.0Hz), 7.58 (s, 1H), 7.48 (br, 2H), 2.12 (s, 3H).

[0164] 5-(5-fluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)-N,N,4-trimethylpyrimidin-2-amine (compound 9): 1 H NMR (DMSO-d6): δ = 8.55 (s, 2H), 8.35 (d, 2H, J = 8.0Hz), 7.91 (d, 2H, J = 8.0Hz), 7.49 (br, 1H), 3.15 (s, 6H).

[0165] 5-(5-fluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)-N,N,4-trimethylpyrimidin-2-amine (compound 10): 1 H NMR (DMSO-d6): δ = 8.54 (s, 1H), 8.47 (s, 1H), 8.38 (d, 2H, J = 8.0Hz), 7.92 (d, 2H, J = 8.0Hz), 7.60-7.54 (m, 2H), 7.30 (d, 1H, J = 4.4Hz), 2.16 (s, 3H).

[0166] 2-(4-(difluoromethyl)phenyl)-5-fluoro-6-(3-methylpyridin-4-yl)-1H-benzo[d]imidazole (compound 11): 1H NMR (DMSO-d6): δ=8.51(s,1H),8.46(s,1H),8.35(d,2H,J=8.0Hz),7.90(d,2H,J=8. 0Hz), 7.63-7.54 (m, 2H), 7.30 (d, 1H, J = 4.4Hz), 7.18 (t, 1H, J = 61.2Hz), 2.16 (s, 3H).

[0167] 6-(2-chloro-6-methylpyridin-3-yl)-5-fluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (compound 12): 1 HNMR (DMSO-d6): δ = 8.37 (d, 2H, J = 8.0Hz), 7.92 (d, 2H, J = 8.0Hz), 7.81 (d, 2H, J = 8.0Hz), 7.60-7.54 (m, 2H), 7.38 (d, 1H, J = 8.4Hz), 2.46 (s, 3H).

[0168] 6-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-fluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (compound 13): 1 H NMR (DMSO-d6): δ = 8.36 (d, 2H, J = 8.0Hz), 7.91 (d, 2H, J = 8.0Hz), 7.57-7.46 (m, 3H), 3.81 (s, 3H), 2.56 (s, 3H).

[0169] 7-Fluoro-6-(2-methylpyrimidin-5-yl)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (compound 14): 1 H NMR (DMSO-d6): δ = 8.92 (s, 2H), 8.41 (d, 2H, J = 8.0Hz), 7.93 (d, 2H, J = 8.0Hz), 7.55 (d, 1H, J = 8.4Hz), 7.43 (d, 1H, J = 7.6Hz), 2.66 (s, 3H).

[0170] 5-Fluoro-6-(6-methylpyridin-3-yl)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (compound 15): 1 H NMR (DMSO-d6): δ = 8.62 (s, 1H), 8.36 (d, 2H, J = 8.0Hz), 7.92 (d, 2H, J = 8.0Hz), 7.88 (d, 1H, J =7.6Hz), 7.67 (d, 1H, J = 7.6Hz), 7.55 (d, 1H, J = 8.0Hz), 7.39 (d, 1H, J = 7.6Hz), 2.47 (s, 3H).

[0171] 4-(5-(5-fluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)morpholine (compound 16): 1 HNMR (DMSO-d6): δ = 13.37 (br, 1H), 8.60 (s, 2H), 8.36 (d, 2H, J = 8.0Hz), 7.91 (d, 2H, J=8.0Hz),7.71(m,1H),7.54(m,1H),3.74(t,4H,J=4.0Hz),3.66(t,4H,J=8.0Hz).

[0172] 5-Fluoro-6-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazolium (compound 17): 1 H NMR (DMSO-d6): δ=8.57(s,2H),8.36(d,2H,J=7.6Hz),7.91(d,2H,J=7.2Hz ),7.71(br,1H),7.59-7.51(m,2H),3.76(m,4H),2.35(m,4H),2.19(s,3H).

[0173] (4-(6-(2-chloropyridin-3-yl)-5-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)(pyrrolidin-1-yl)methyl ketone (compound 18): 1 H NMR (DMSO-d6): δ=13.30(br,1H),8.47(s,1H),8.18(d,2H,J=7.6Hz),7.95(t,1H,J=6. 4Hz), 7.69 (d, 2H, J = 7.6Hz), 7.62-7.46 (m, 3H), 3.48-3.40 (m, 4H), 1.88-1.78 (m, 4H).

[0174] 5-Fluoro-6-(1-Isopropyl-1H-pyrazol-5-yl)-2-(4-(Methylsulfonyl)phenyl)-1H-benzo[d]imidazolium (Compound 19): 1 H NMR (DMSO-d6): δ = 8.40 (d, 2H, J = 8.0Hz), 8.1 (d, 2H, J = 8.4Hz), 7.60 (m, 2H), 7.5 (d, 1H, J=1.8Hz), 6.32 (d, 1H, J=1.8Hz), 4.31 (dt, 1H, J=6.4Hz), 1.31 (d, 6H, J=6.4Hz).

[0175] 4-(5-(5-fluoro-2-(4-(methanesulfonyl)phenyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)morpholine (compound 20): 1 H NMR (DMSO-d6): δ = 8.61 (s, 2H), 8.40 (d, 2H, J = 8.4Hz), 8.08 (d, 2H, J = 8.4Hz), 7.72(br,1H),7.56(m,1H),3.75(m,4H),3.67(q,4H,J=4.4Hz),3.26(s,3H).

[0176] 4-(5-fluoro-6-(1-isopropyl-1H-pyrazole-5-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 21): 1 H NMR (DMSO-d6): δ = 8.40 (d, 2H, J = 8.4Hz), 7.92 (d, 2H, J = 8.4Hz), 7.60-7.56 (m, 2H), 7 .60 (s, 1H), 6.32 (d, 1H, J = 1.6Hz), 4.95 (m, 1H), 2.64 (s, 6H), 1.40 (d, 6H, J = 6.4Hz).

[0177] 4-(6-(2-amino-4-methylpyrimidin-5-yl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 22): 1 H NMR (DMSO-d6): δ = 8.39 (d, 2H, J = 8.0Hz), 8.05 (s, 1H), 7.91 (d, 2H, J = 8.0Hz), 7.50-7.42 (m, 2H), 6.65 (s, 2H), 2.59 (s, 6H), 2.13 (s, 3H).

[0178] 1-(4-(5-fluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethane-1-one (compound 23): 1 H NMR (DMSO-d6): δ = 8.36 (d, 2H, J = 8.0Hz), 7.92 (d, 2H, J = 8.0Hz), 7.55 (m, 2H), 2.62 (s, 3H), 2.38 (s, 3H), 2.12 (s, 3H).

[0179] 6-(3,5-Dimethyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)-5-fluoro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazolium (compound 24): 1H NMR (DMSO-d6): δ = 8.36 (d, 2H, J = 8.0Hz), 7.92 (d, 2H, J = 8.0Hz), 7.55 (m, 2H), 3.53 (s, 3H), 2.34 (s, 3H), 2.12 (s, 3H).

[0180] 4-(4,5-Difluoro-6-(1-isopropyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 25): 1 H NMR (DMSO-d6): δ = 8.41 (d, 2H, J = 8.4Hz), 7.90 (d, 2H, J = 8.4Hz), 7.60 (s, 1H), 7.56 (d, 1H, J=1.6Hz), 6.33 (d, 1H, J=1.6Hz), 4.98 (m, 1H), 2.63 (s, 6H), 1.39 (d, 6H, J=6.4Hz).

[0181] 4-(5-fluoro-6-(4-methyl-2-morpholinopyrimidin-5-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 26): 1 H NMR (DMSO-d6): δ = 8.42 (d, 2H, J = 8.0Hz), 8.09 (s, 1H), 7.98 (d, 2H, J = 8.0Hz) ,7.54(m,2H),3.76(m,4H),3.65(q,4H,J=4.4Hz),2.63(s,6H),2.15(s,3H).

[0182] 4-(6-(2-amino-4-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 27): 1 H NMR (DMSO-d6): δ = 8.40 (d, 2H, J = 8.4Hz), 8.07 (s, 1H), 7.92 (d, 2H, J = 8.4Hz), 7.51 (s, 1H), 6.67 (s, 2H), 2.59 (s, 6H), 2.15 (s, 3H).

[0183] 4-(6-(4-chloro-2-methylpyrimidin-5-yl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 28): 1 H NMR (DMSO-d6): δ = 8.71 (s, 1H), 8.41 (d, 2H, J = 8.4Hz), 7.90 (d, 2H, J = 8.4Hz), 7.61 (s, 1H), 2.74 (s, 3H), 2.62 (s, 6H).

[0184] 4-(6-(2,4-dimethylpyrimidin-5-yl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 29): 1 H NMR (DMSO-d6): δ = 8.51 (s, 1H), 8.40 (d, 2H, J = 8.4Hz), 7.92 (d, 2H, J = 8.4Hz), 7.59 (m, 2H), 2.64 (s, 6H), 2.60 (s, 3H), 2.31 (s, 3H).

[0185] 4-(5-chloro-6-(4-chloro-2-methylpyrimidin-5-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 30): 1 H NMR (DMSO-d6): δ = 8.65 (s, 1H), 8.40 (d, 2H, J = 8.4Hz), 8.29 (d, 2H, J = 8.4Hz), 7.63 (s, 1H), 7.51 (s, 1H), 2.73 (s, 3H), 2.62 (6H).

[0186] 4-(6-(2-amino-4-methylpyrimidin-5-yl)-5-chloro-4-fluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 31): 1 H NMR (DMSO-d6): δ = 8.41 (d, 2H, J = 8.4Hz), 8.05 (s, 1H), 7.90 (d, 2H, J = 8.4Hz), 7.48 (s, 1H), 6.67 (s, 2H), 2.63 (s, 6H), 2.16 (s, 3H).

[0187] 4-(5-fluoro-6-(4-methoxy-2-methylpyrimidin-5-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 32): 1 H NMR (DMSO-d6): δ = 8.61 (s, 1H), 8.39 (d, 2H, J = 8.0Hz), 7.92 (d, 2H, J = 8.0Hz), 7.56 (m, 2H), 4.01 (s, 3H), 2.63 (s, 6H), 2.61 (s, 3H).

[0188] 4-(5-fluoro-6-(4-(trifluoromethyl)pyrimidin-5-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 33): 1H NMR (DMSO-d6): δ=9.34(s,1H),9.12(s,1H),8.42(d,2H,J=7.6Hz),7.92(d,2H,J=7.6Hz),7.68(s,1H),7.62(s,1H),2.60(s,6H).

[0189] 4-(6-(2-amino-4-isopropylpyrimidin-5-yl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 34): 1 H NMR (DMSO-d6): δ = 8.41 (d, 2H, J = 8.4Hz), 8.07 (s, 1H), 7.90 (d, 2H, J = 8.0Hz), 7. 53-7.46(m,2H),6.62(br,2H),2.62(s,6H),2.38(m,1H),1.36(d,6H,J=1.2Hz).

[0190] 4-(6-(2-amino-4-methylpyrimidin-5-yl)-4-chloro-5-fluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 35): 1 H NMR (DMSO-d6): δ = 8.39 (d, 2H, J = 8.4Hz), 8.06 (s, 1H), 7.90 (d, 2H, J = 8.4Hz), 7.45 (s, 1H), 6.62 (s, 2H), 2.63 (s, 6H), 2.15 (s, 3H).

[0191] 4-(5-fluoro-6-(6-fluoro-4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl)benzenesulfonamide (compound 36): 1 HNMR (DMSO-d6): δ = 8.32 (d, 2H, J = 8.0Hz), 8.14 (s, 1H), 7.74 (d, 2H, J = 8.0Hz), 7.5 0(d,1H,J=1.2Hz),7.47(d,1H,J=1.2Hz),6.97(s,1H),6.38(br,2H),2.30(s,3H).

[0192] 4-(5-fluoro-6-(6-fluoro-4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-N-methylbenzenesulfonamide (compound 37): 1H NMR (DMSO-d6): δ = 8.37 (d, 2H, J = 8.4Hz), 8.12 (s, 1H), 7.73 (d, 2H, J = 8.4Hz), 7.50 (d, 1H) ,J=1.2Hz),7.46(d,1H,J=1.2Hz),7.01(s,1H),5.94(br,1H),2.58(s,3H),2.32(s,3H).

[0193] 4-(5-fluoro-6-(1-(2-fluoropropane-2-yl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 38): 1 H NMR (DMSO-d6): δ = 8.43 (d, 2H, J = 8.4Hz), 7.91 (d, 2H, J = 8.4Hz), 7.63-7.56 (m ,2H),7.60(s,1H),6.32(d,1H,J=1.6Hz),2.63(s,6H),1.43(d,6H,J=6.4Hz).

[0194] 4-(5-fluoro-6-(6-methoxy-4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 39): 1 H NMR (DMSO-d6): δ = 8.38 (d, 2H, J = 8.0Hz), 8.0 (s, 1H), 7.99 (d, 2H, J = 8.0Hz), 7.93-7.91 (m, 2H), 6.79 (s, 1H), 3.88 (s, 3H), 2.62 (s, 6H), 2.11 (s, 3H).

[0195] 4-(6-(6-amino-4-chloropyridin-3-yl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 40): 1 H NMR (DMSO-d6): δ = 8.36 (d, 2H, J = 8.0Hz), 7.82 (d, 2H, J = 8.0Hz), 7.50 (d, 1H, J = 8. 0Hz), 7.42 (d, 1H, J = 8.0Hz), 7.38 (s, 1H), 7.26 (s, 1H), 6.48 (s, 2H), 2.60 (s, 6H).

[0196] 4-(5-fluoro-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylbenzenesulfonamide (compound 41): 1H NMR (DMSO-d6): δ = 11.80 (br, 1H), 8.35 (d, 2H, J = 8.0Hz), 7.92 (d, 2H, J = 8.0Hz), 7.51- 7.48 (m, 2H), 7.34 (d, 1H, J = 8.0Hz), 6.22 (d, 1H, J = 8.0Hz), 2.59 (s, 6H), 2.05 (s, 3H).

[0197] Example 2

[0198] This embodiment relates to the relationship between the structure and activity of benzimidazole compounds containing aromatic substituents. Specifically, the biochemical activity of the benzimidazole compounds containing aromatic substituents described herein as sEH enzyme inhibitors was evaluated through in vitro and cellular experiments.

[0199] The experimental procedures for evaluating in vitro biochemical activity are as follows.

[0200] The substrate used in the evaluation experiments was epoxyeicosatrienoic acid (EET). The solutions used in the evaluation experiments were: Bis / Tris HCl 25mM pH 7.0; buffer A was Bis / Tris HCl 25mM pH 7.0 containing 0.1 mg / mL BSA; and buffer B was Bis / Tris HCl 25mM pH 7.0 containing 36.3 mM ZnSO4.

[0201] The specific steps of the evaluation experiment included: filling all wells of a black 96-well plate with 79 μL of buffer A, followed by adding 1 μL of a benzimidazole compound solution containing an aromatic substituent to each well. Then, 10 μL of sEH (1 μM) buffer A solution was added to the wells. After pre-incubating at room temperature for 90 min, 10 μL of EET (10 μM) buffer A solution was added to trigger the reaction. The reaction was then carried out outdoors for 60 min, followed by quenching the reaction with 15 μL of buffer B and 180 μL of acetonitrile. The plate was then centrifuged at high speed and filtered for later use.

[0202] The concentration of EET in the samples was detected using LC-MS. The final IC50 was calculated using Graphpad Prism software based on three independent experiments. 50 .

[0203] The experimental procedures for cellular-level assessment are as follows.

[0204] The substrate used in the cellular assessment assay was epoxyeicosatrienoic acid (EET). The solution used in the cellular assessment assay was FBS-free OPTI-MEM (hereinafter referred to as buffer C).

[0205] The cellular assessment experiment included the following steps: In a 96-well cell culture plate, all wells were filled with 90 μL of HepG2 cells, resulting in a cell density of approximately 10,000 cells / mL. Then, 10 μL of the benzimidazole compound containing an aromatic substituent was added to each well. After pre-incubation in a cell culture incubator for 30 min, 10 μL of EET (10 μM) buffer C solution was added to trigger the reaction. The cell culture plate was incubated for 120 min, then centrifuged at 1000g for 10 min, and the supernatant was collected for later use.

[0206] The concentration of EET in the samples was detected using LC-MS. The final IC50 was calculated using Graphpad Prism software based on three independent experiments. 50 .

[0207] The IC50 values ​​of compounds 1-41 against soluble epoxide hydrolases were obtained through in vitro biochemical activity evaluation experiments. 50 See Table 1.

[0208] As shown in Table 1, the IC50 values ​​of the benzimidazole compounds containing aromatic substituents described in this paper are [data missing]. 50 The concentrations in the nM range or even lower indicate extremely high inhibitory activity against soluble epoxide hydrolases. Compared to benzimidazole compounds with aromatic substituents including the 4-trifluoromethylphenyl structure, benzimidazole compounds with aromatic substituents including the 4-sulfonamide phenyl structure not only effectively maintain (increase) the activity of the compound but also significantly reduce its lipophilicity and increase its water solubility, thereby improving the pharmacokinetic properties of this type of compound. By choosing different structures, different chemophysical properties of the compound, such as lipophilicity, partition coefficient, and CNS (central nervous system) pharmacological characteristics, can be easily adjusted to achieve different therapeutic purposes.

[0209] The above description of the embodiments is intended to enable those skilled in the art to understand and apply this application. It will be apparent to those skilled in the art that various modifications can be easily made to these embodiments, and the general principles described herein can be applied to other embodiments without creative effort. Therefore, this application is not limited to the embodiments described herein, and any improvements and modifications made by those skilled in the art based on the disclosure of this application without departing from the scope and spirit of this application are within the scope of this application.

Claims

1. A benzimidazole compound containing an aromatic substituent, and a pharmaceutically acceptable salt thereof, characterized in that, The benzimidazole compounds containing aromatic substituents are selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , and 。 2. The use of a pharmaceutically acceptable salt of a benzimidazole compound containing an aromatic substituent as described in claim 1 for the preparation of a soluble epoxide hydrolase inhibitor.

3. A pharmaceutical composition comprising a benzimidazole compound containing an aromatic substituent as described in claim 1, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or excipient.

4. A kit comprising a benzimidazole compound containing an aromatic substituent as claimed in claim 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 3.

5. Use of a pharmaceutically acceptable salt of a benzimidazole compound containing an aromatic substituent as described in claim 1 in the preparation of a medicament for treating sEH-mediated diseases.

6. A method for preparing a benzimidazole compound containing an aromatic substituent as described in claim 1, characterized in that, The method includes the following steps: S1: React the halo-o-phenylenediamine precursor with the benzaldehyde precursor to obtain the benzimidazole intermediate; S2: React the benzimidazole intermediate with the boric acid precursor to obtain the benzimidazole compound containing aromatic substituents as described in claim 1; The halo-o-phenylenediamine precursor has a structure represented by the following general formula (1): General formula (1), The benzaldehyde precursor has a structure represented by the following general formula (2): General formula (2), The benzimidazole intermediate has a structure represented by the following general formula (3): General formula (3), The boric acid precursor is Ar1-B(OH)2, or has a structure represented by the following general formula (4): General formula (4), Where M represents halogen.

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